-This is a resubmission of a grant application proposing to search extensively for mutations that interfere with the normal process of epidermal and in particular palmoplantar keratinization. The project consists of three integrated and interdependent aims. The first one is to search for mutations in eleven candidate genes in a small number of families with a characterized inherited keratoderma. Specifically, the genes are loricrin, involucrin, envoplakin, desmoplakin, plakoglobin, desmogleins 1, 2, 3, desmocollins 1, 2 and 3, and the diseases include Netherton's, Mal-de-Maleda, Vohlwinkel's, Kindler/Weary, erythrokeratoderma, nonepidermolytic PPK, PRP, and eight others for which 1 to 10 families have been enlisted into studies. The second is to identify the mutated genes in large pedigrees with well-characterized, dominant, and fully penetrant keartodermas, one with EB superficialis, the other "Novel Acantholytic Disease." The pedigrees are so large that if the mutations do not map in the region of candidate genes, the first look, random polymorphisms will be used to saturate the map and localize the mutations. The third is to isolate and characterize genes that play a role in epidermal differentiation. Some of these have been cloned at the cDNA level, but the genomic organization, i.e., intron-exon boundaries, is unknown. Others will be obtained from the results of the Specific Aim 2, namely, genes identified as mutated in EB superficialis, and the Novel Acantholytic Disease will be cloned and characterized.